1. Field of the Invention
The present invention pertains to a process of preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofunanosyl sulfonates, which are useful as intermediates in the preparation of beta nucleosides, which are anti-tumor agents. Specifically, the present invention pertains to a process of converting beta-2-deoxy-2,2-difluoro-D-ribofunanosyl sulfonates to alpha-2-deoxy-2,2-difluoro-D-ribofunanosyl sulfonates, which may be further converted to desired beta nucleosides.
2. Description of the Related Art
Stereoselective process for preparing a nucleoside involves stereochemical inversion of a furanose sugar at the anomeric position, therefore when beta-nucleoside is the desired product, an appropriate sugar intermediate enriched in alpha anomer is preferably used as the substrate in the glycosylation reaction. For example, the known substance, gemcitabine, is a nucleoside in the β-configuration and, therefore, it may preferably be prepared by inversion of the center resulting from SN2 displacement of a blocked cytosine on the appropriate sugar sulfonate intermediate in the α-configuration.
Currently known technology results in the preparation of alpha-anomer enriched sulfonate esters by the reaction of a blocked sugar lactol with a sulfonating reagent at low temperatures. The desired alpha-anomer can be crystallized in enhanced purity but in low yield. The remaining material is usually a mixture of alpha and beta anomers from which enriched alpha-anomer can not easily be isolated. Without an effective method of recovering this material and converting it to the desired alpha enhanced anomer, the yield of alpha anomer is low, and the commercial viability of the process is in jeopardy.
U.S. Pat. No. 5,256,798 discloses a process of preparing an alpha-anomer enriched ribofuranosyl sulfonate by treating a beta-anomer ribofuranosyl sulfonate with a source of conjugate anion of a sulfonic acid (i.e., sulfonate salt) at an elevated temperature in an inert organic solvent. However the difficulty of solubilizing the conjugate anion of sulfonic acid in a solvent and the necessity of removal of the solvent and aqueous workup limit the usefulness of this procedure. Therefore there is still a need for a more efficient procedure.